ABSTRACT
A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower C(max) versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.
ABSTRACT
EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.
ABSTRACT
OBJECTIVE: DepoFoam bupivacaine (DB) is in development for prolonged postoperative analgesia. Studies were conducted to evaluate the potential local and systemic toxicity and any effect on wound healing after wound infiltration. METHODS: The model simulates an inguinal hernia (skin incision â¼2.5 and 5.5 cm). Animals (four/sex/group of each species) received DB 9, 18 or either 25 or 30 mg/kg, bupivacaine solution (B(sol); 7.5 mg/ml, 9 mg/kg) or saline. DB was given at 0.6, 1.2 and 1.0 or 1.2 ml/kg, respectively, and B(sol) or saline at 1.2 ml/kg. Each dose was infiltrated in small fractions on Day 1. End points included histology on Days 3 and 15. Wound healing was recorded on Day 2 through Day 15. RESULTS: There was no adverse effect in either species. Notably, granulomatous inflammation was noted in surgical sites from 8 of 24 rabbits in the DB groups only. Based on the minimal to mild severity on Day 15, this was considered a normal reaction against the liposomes. Except for granulomatous inflammation, there were no differences in overall incidence or severity of histologic changes in the sites dosed to DB, saline or B(sol). CONCLUSIONS: The data reported here are the first demonstration of the safety of DB in toxicology species.
Subject(s)
Anesthetics, Local/pharmacology , Bupivacaine/pharmacology , Pain, Postoperative/drug therapy , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacokinetics , Anesthetics, Local/therapeutic use , Animals , Bupivacaine/administration & dosage , Bupivacaine/pharmacokinetics , Bupivacaine/therapeutic use , Delayed-Action Preparations , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Female , Hernia, Inguinal/surgery , Injections , Liposomes , Male , Rabbits , Random Allocation , Wound Healing/drug effects , Wound Healing/physiologyABSTRACT
17α-Ethynyl-androst-5ene-3ß, 7ß, 17ß-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3ß,7ß,17ß-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents.
